An analysis of the CMC/GMP regulatory framework among the Association of South East Asian Nations (ASEAN) shows significant progress in moving toward a more cohesive and harmonized approach, although differences remain in individual country requirements and procedures.
ASEAN implemented a common technical document (“ACTD”), similar to the ICH CTD, in 2009, and is developing a common set of core CMC guidelines applicable across the member countries.
A mutual recognition agreement (MRA) on GMPs signed by all the ASEAN countries in 2009, which provides for the sharing of inspection and registration information, represents another recent step forward in the cooperation effort. The MRA becomes effective at the beginning of 2011. Increased interaction with the Pharmaceutical Inspection Cooperation Scheme (PIC/S) is also helping drive GMP alignment on an internal and inter-regional level.
The harmonization of pharmaceutical regulation is an important component in the association’s primary objective of facilitating elimination of technical barriers to free trade while strengthening regulatory oversight.
The 10 member countries include six that are more dominant players in the pharmaceutical arena – Thailand, Singapore, Indonesia, Malaysia, Vietnam and the Philippines – and four others – Myanmar, Cambodia, Brunei and Laos. The combined population is over 500 million.
ISPE’s Asia Pacific Focus Group Shares Insights
The progress made in achieving harmonization in the ASEAN region and some of the remaining gaps and challenges for global pharmaceutical firms in interacting with the individual countries and meeting application and GMP requirements were addressed at a session of the ISPE annual meeting in Orlando, Florida in early November.
The session focused on new and emerging regulations and guidelines and provided a forum for ISPE’s Asia Pacific Focus Group to share its knowledge of CMC and GMP experiences in these countries.
In introducing the session, Pfizer Global Regulatory CMC Executive Director Chi-wan Chen explained that the focus group was formed in mid-2009 to bring together regulatory CMC/GMP professionals from various companies that have responsibilities in either portfolio filing and/or regulatory policy in the Asia-Pacific area to create a networking/experience-sharing forum. The Orlando session was the focus group’s first opportunity to share its discussions in a public forum.
At the session, Eli Lilly Principle Consultant for Regulatory Affairs Susan Stolz and GlaxoSmithKline (GSK) CMC Advocacy and Regulatory Intelligence Director Bekki Komas provided the focus group’s insights into current efforts taking place in the ASEAN region.
Chen – a former key drug CMC review official – followed with an analysis of the current situation in China and how its regulatory processes are evolving toward a more Western model (IPQ “In the News” November 29).
Other forum members addressing CMC/GMP developments across the Asia/Pacific region at the session were Lilly CMC Global Regulatory Affairs Director Jeffrey Ferguson (on Korea), Merck Associate Director Pramod Kotwal (on Japan), and Bristol-Myers Squibb Executive Director Mark Rosolowsky (on Taiwan and India).Independent Review Processes Aligned on Standards and Procedures
Impacting the rate at which the ASEAN harmonization process is unfolding is the need to have unanimity before common standards and procedures are adopted.
“They want to respect each other’s sovereignty, so they want to make sure that all are in agreement before they move on,” Lilly’s Stolz explained. She drew a contrast with European harmonization where the countries involved “are more about moving forward for the good of the order and not as much focused on each other’s sovereignty.”
While the ASEAN goal is to adopt similar standards, each of the ten countries has its own independent review process, and companies thus work with each country’s health authority independently – again, unlike the centralized system that has been developed in Europe. Stolz recognized that dealing with ten independent assessors in the region “has some challenges.”
In general, the authorities in ASEAN require a summarized core dossier and a Certificate of Pharmaceutical Product (CPP) from an outside regulatory authority such as the FDA or EMA to begin the registration process. A CPP certifies that the quality, safety and efficacy of the product has been reviewed and the product cleared for marketing by that authority.
Unlike the other nine ASEAN countries, Singapore also has a non-CPP registration pathway and the ability to do an independent assessment.
Stolz noted that the requirements among these countries for specific CMC information in the dossiers are increasing.
She cited information on how a product is packaged as an example. “Ten years ago or so we could say that it was put in a glass vial with a rubber stopper, and that was an acceptable level of detail in those markets. Now they might expect us to explain the dimensions and the composition of the rubber stopper and what testing is being performed – either by the vendor or upon incoming release.”
The regulatory processes in the ASEAN countries also share relatively lengthy review and approval timeframes.
Companies have to wait for a major market approval and the issuance of the certificate before the review process in these countries can be started, “so it can be quite lengthy,” Stolz explained – averaging 9-18 months for new product approval.
ASEAN CTD Models ICH With Some Organizational Differences
In its “technical cooperation” effort to align on dossier content/format and CMC/GMP guidance, ASEAN has assigned different countries to take the lead on particular facets (see box at right – the documents in blue are discussed further below). Indonesia, for example, has taken the lead on the quality section of the ACTD.
While developed with the ICH CTD as a model, the ACTD does have some structural differences. As a result, Stoltz commented, CMC regulatory professionals have to manage additional documents “because the information is not located in the exact same location between the two formats.”
For example, in the ACTD, the pharmaceutical development section is located in a section titled P.2.2, whereas ICH requests that information in its section 3.2.P.2.1.
Not all ASEAN countries require the ACTD format. Singapore and the Philippines will accept either the ACTD or the ICH CTD, although Stolz’s experience suggests that approval in the Philippines may be faster if the ACTD format is used. Thailand, on the other hand, requires an ACTD for new products and generics, but not for variations and renewals.
“While it starts out that ten countries say they want to have this common format, you start to see that it is really not all ten. You may not even be marketing in all ten countries, and the ones that you are submitting in do not necessarily need it,” Stolz concluded.
Stabililty Draft Released in July; BA/BE and Variations Guides Progressing
ASEAN countries have focused their guidance harmonization efforts in five primary areas: ● stability studies ● bioavailability/bioequivalence (BA/BE) ● variations ● process validation, and ● analytical validation.
The stability guideline, first approved in 2005, was extensively revised and released in draft form in July.
Much of the revised material was adopted from the WHO (2009) and ICH Q1E stability guidelines, including the directions on on-line testing, semi-permeable container testing, bacterial endotoxin testing and storage conditions.
In the case of the number of batches required for stability studies, ASEAN has chosen not to duplicate the WHO/ICH standards, but to remain with its 2005 requirements: two batches for conventional dosage forms; three for critical dosage forms; and 12 months of real-time data and six months accelerated data for variations, with no relief for changing packaging components to provide more protection.
The draft prescribes the stringent WHO Zone IVb (“tropical wet”) standard for stability testing at 30°C and 75% relative humidity.
ASEAN implementation of the Zone IVb requirements started with new products in January 2009. Existing products must have 30°C/75% RH by their 2012 renewal. However, GSK’s Komas noted that “each country may have its own different implementation expectations.”
Komas also noted that some large companies have been successful in lobbying for 30°C/65% RH data when supported by moisture vapor transmission rate data.
The BA/BE guideline was originally adopted in 2004 with a Q&A document released in 2009, and is currently undergoing revision.
The document principles apply to post-approval changes and pre-approval bridging studies in formulations of different strengths, and to generics.
The revision includes harmonization with the internationally-recognized Biopharmaceutics Classification System (BCS), which defines the drug solubility/permeability class based on dissolution data and pharmacopeia test methodology.
ASEAN’s variation guideline is in its fifth draft, with a comment period that ended in September.
New in the draft are definitions of major and minor variations as well as a “do and tell” notification. The modifications allow “greater flexibility in terms of making changes in less time,” Komas noted.
The draft proposes an evaluation timeline for a major variation of 90 working days and 30 days for minor variations. The “do and tell” provision allows firms to make certain changes and report them using a system that is similar to the US annual reporting system.
When the guideline is finalized, each country will propose its own timeline for regulatory agency evaluation of applications and implementation of the variation provisions. Biotech and biosimilar products were not included in the scope of this draft.
Individual Countries Have Some Unique Concerns
While aligning on the dossier information, in some cases the countries do have individual requirements. Komas reviewed the Asia Pacific forum’s analysis of some of the key differences.
Indonesia has a pork decree which specifies that porcine content has to be clearly stated on the outer carton – reflecting the morays of the high-Muslim population.
The labeling must state that “the manufacturing process involves substance that is sourced from swine and has been purified so that it is not detected in the final product.” The decree also applies for products which have a manufacturing process containing materials sourced from pigs, even if already purified, such as enzymes commonly used in the biotech industry.
Malaysia has some unique requirements around analytical and process validation.
“In most of the new submissions lately we have been experiencing a lot of detailed questions on methods and method validation – even for compendial methods where you would not expect to provide validation,” Komas pointed out. Recent application reviews, she said, have included additional method validation questions such as column detail, raw data results and calculation directions that are normally provided upon inspection.
Sponsors have also been requested recently to provide validation summary reports for manufacturing performance qualification, which is outside of the relevant guideline.
The GSK official noted that Malaysia has been using a checklist during its reviews. “We personally have received a copy of that checklist lately and are using that to try to provide better information up front or better justification, so that we do not get those questions upon review,” she said.
Other differences in what the various agencies are seeking include: a specific format for the Quality Overall Summary (Singapore); and signatures on dossier pages and a requirement for a local registration study (Vietnam).
New Task Force, PIC/S Interaction Driving toward GMP Cooperation
There are also differences in the GMP requirements and documentation requested within the ASEAN community. For example, the agencies may request a GMP certificate along with the CPP.
Recognizing their differences in GMP requirements, ASEAN has formed a task force to explore further harmonization.
Lilly’s Stoltz noted that industry has proposed that rather than focusing on GMP certification, ASEAN could focus instead, for example, on using the European GMP database. She cited the proposal as “an example of ways that industry is trying to help push them to look to standards that are out there already rather than having the ASEAN countries develop their own.”
Discussion is also underway within ASEAN to incorporate cross-referencing within the region so the GMP information does not need to be requested by every country.
An important development in ASEAN’s path toward both internal and international GMP cooperation is its increasing relationship with PIC/S.
The health agencies of Malaysia and Singapore are among the 37 current PIC/S members, and Indonesia and Thailand have applied for membership.
Malaysia’s National Pharmaceutical Control Bureau (NPCB) hosted the PIC/S committee meeting and annual training seminar in Kuala Lumpur, held November 8-11 (IPQ “In the News” Dec. 29).
The meeting was marked by the formal acceptance of FDA as the 38th “participating authority” beginning January 1. The Ukranian State Inspectorate for Quality Control of Medicines was accepted as the 39th PIC/S member beginning in 2011.
Delegations from ASEAN and PIC/S met the following day to discuss a pathway for initiating cooperation between the two organizations – for example, in terms of training.
The PIC/S delegation pointed out at the meeting that its training activities were open to inspectors from the ASEAN authorities and suggested that future PIC/S training courses could be run in the Australasian region in order to facilitate participation of ASEAN inspectors.
The ASEAN representatives, in turn, noted that as part of its GMP MRA becoming effective in 2011 the ASEAN Secretariat will maintain a list of inspection services fulfilling the MRA’s requirements – either through PIC/S membership or by a PIC/S-equivalent GMP inspection system.
The PIC/S delegation offered to provide advice to the ASEAN authorities on how to reach PIC/S membership requirements and invited the ASEAN agencies and secretariat to the 40th PIC/S anniversary meeting in late May in Geneva.
At the ISPE session, Stoltz and Komas both pointed to the positive impact of the ASEAN country participation in PIC/S on industry.
Noting that PIC/S sets standards for how inspections and GMP documentation need to take place, they pointed out that further ASEAN harmonization around these international standards, guidances and inspector training will lesson the problems of having to deal with the individual country differences and potentially reduce inspection duplication.
Komas stressed that the ASEAN GMP MRA will also serve to reduce duplication of GMP audits within the region. She summarized the overall benefits of the MRA: “It will save time, resources and costs for regulators and industry. It will facilitate trade in medicinal products across the region. It will give quicker access to medical products to our patients. It will make the ASEAN region more competitive with countries such as India and China in the large markets.”
ASEAN’s goal, Komas noted, is a single market for the region by 2020. “This is an incredible market that is emerging,” the GSK official stressed, and industry has “a lot of opportunities to influence those markets with our responses” to the guidance documents that the region is formulating.
In its report on the Kuala Lumpur meeting, PIC/S outlined the progress of the pending membership applications, including those of Indonesia’s National Agency for Drug and Food Control (NADFC) and the Thai FDA.
A PIC/S inspection team had conducted an on-site inspection of NADFC the week prior to the November meeting and found that the agency is meeting most of the PIC/S membership requirements. A follow-up visit is scheduled for 2011.
The report explains that the Thai FDA had postponed the completion date for its corrective action plan from 2012 to 2015 – beyond the six-year timeframe for acceding to PIC/S, which expires in 2012. The PIC/S committee decided that a follow-up visit would be made to the Thai FDA during 2011, if the agency reconfirmed its commitment to complete the plan by 2012.